Xanthophylls are a large group of carotenoids containing oxygen in molecules in addition to carbon and hydrogen. Astaxanthin, a xanthophyll carotenoid, is a natural antioxidant that is produced in many biological organisms (Hussein et al., 2006). It occurs naturally in certain algae and causes the pink or red color in salmon, trout, lobster, shrimp, and other seafood. While astaxanthin is a natural dietary component, it can also be used as a food supplement. The U.S. Food and Drug Administration (FDA) has approved astaxanthin as a food coloring (or color additive) for specific uses in animal and fish foods. The European Commission considers it a food dye and it is given the E number E161j. Natural astaxanthin is generally recognized as safe (GRAS) by the FDA, but as a food coloring in the United States it is restricted to use in animal food only.
The biological activities of astaxanthin have been tested in many animal models and clinical tests. Astaxanthin blocks the aerobic metabolism-generated free radicals, such as hydroxyls, peroxides and reactive oxygen species, thus preventing abnormal DNA damage (Higuera-Ciapara et al., 2006). Further studies have also demonstrated that astaxanthin contributes to immune response (Kim et al., 2009; Park et al., 2010). Participants who received astaxanthin daily for 8 weeks showed upregulating mitogen-induced lymphoproliferation, increased natural killer cell cytotoxic activity, and increased total T and B leukocytes. U.S. Pat. No. 6,773,708 B1 discloses the use of xanthophylls such as astaxanthin for the treatment of autoimmune diseases, chronic viral and intracellular bacterial infections by suppressing excessive Th1 cell mediated immune responses, and stimulating Th2 cell mediated immune responses in a patient during ongoing infection and/or inflammation in said patient.
Oral administration of astaxanthin inhibits thrombosis in vascular endothelial injury mouse models and in stroke-prone spontaneously hypertensive rats (Khan et al., 2010; Sasaki et al., 2011). CN 101361726 A discloses that astaxanthin can improve behavioral symptoms caused by cerebral ischemia reperfusion injury of rats, decrease the volume of cerebral infarction and lower the cerebral edema of cerebral ischemic rats, and thus can be used for preparing drugs for preventing and curing brain stroke.
In addition, astaxanthin also protects neuronal cells. Treatment with astaxanthin ameliorates neuroinflammation and early brain injury by activating nuclear factor erythroid-related factor 2 and the antioxidant responsive element (Nrf2-ARE) pathway after subarachnoid hemorrhage (Wu et al., 2014; Zhang et al., 2014a; Zhang et al., 2014b). More importantly, astaxanthin penetrates the natural blood-brain barrier (BBB) and thus can be used in treating brain neuronal diseases (Wu et al., 2014). EP1 867 327 A1 discloses a neurocyte protective agent comprising astaxanthin and/or an ester thereof capable of alleviating mitochondrial dysfunction and oxidative stress in neurocytes. The neurocyte protective agent is effective in protecting against the degeneration of dopaminergic neurons of the substantia nigra and noradrenergic neurons of the locus ceruleus, and it is suggested that the neurocyte protective agent can be used for Parkinson's disease.
Astaxanthin is also suggested as a potential anti-tumor compound. It inhibits hamster oral cancer cell growth by blocking STAT, ERK or PI3K/Akt signaling (Kavitha et al., 2013; Kowshik et al., 2014). It was also reported that the treatment of astaxanthin induces mitochondria-depended apoptosis in hepatocellular carcinoma cells (Song et al., 2011). U.S. Pat. No. 6,277,417 B1 discloses that astaxanthin can inhibit the activity of the enzyme 5α-reductase and thus suggests that it can be used for treating or preventing disorders resulting from the activity of the enzyme, in particular benign prostate hyperplasia and prostate cancer.
The adrenal gland, located superiorly to the kidney, consists of the outer adrenal cortex and the inner medulla parts (Else et al., 2014). The adrenal cortex secretes several steroids such as glucocorticoid and mineralocorticoid to regulate the metabolic homeostasis in the body. Adrenocortical carcinoma is a rare disease, with incidence of 1 to 2 per million people every year. It is an aggressive tumor and is often metastasized to other organs, and the overall survival rate is only 20-35% within 5 years. Tumors occurring in the adrenal cortex may induce aberrant secretion of steroids and show symptoms similar to Cushing's syndrome and virilization (Erickson et al., 2014). Several methods are used in the treatment of adrenocortical carcinoma, e.g., complete surgical excision, radiation therapy and combined chemotherapy (the combination of anti-tumor drugs: cisplatin, doxorubicin and etoposide). To date, there is no single method that can effectively block adrenocortical tumor cell growth. It is desirable to develop a therapeutic agent that can safely and effectively treat adrenocortical carcinoma.
Osteosarcoma is the most common histological form of primary bone cancer. It is most prevalent in children and young adults. Mifamurtide (MEPACT®) is currently approved in Europe for the treatment of osteosarcoma. A combination of high-dose methotrexate with leucovorin rescue, intra-arterial cisplatin, adriamycin, ifosfamide with mesna, BCD (bleomycin, cyclophosphamide, dactinomycin), etoposide, and muramyl tripeptide may also be used for the treatment of osteosarcoma.
Glioblastoma multiforme (GBM) is one of the most severe malignant gliomas. GBM is considered incurable, and is associated with high morbidity and mortality, with a median survival of 15 months following several treatments (Aldape et al., 2015; Alifieris and Trafalis, 2015). Temozolomide (TEMODAR®) is currently approved in Europe and the United States for the treatment of GBM. Temozolomide is an alkylating drug indicated for the treatment of adult patients with newly diagnosed GBM concomitantly with radiation therapy and then as maintenance treatment. Several aggressive combination therapies are currently used in treating GBM, such as maximal-safe surgical resection, radiation therapy and temozolomide treatment (Stupp et al., 2009). Many GBM patients respond poorly to the conventional chemotherapy and radiation therapy. The prognosis falls in a poor survival range of 12-15 months (median 14.6 months).
U.S. Pat. No. 8,632,825 B2 discloses the use of tetrahydrocannabinol (THC) and cannabidiol (CBD) in the manufacture of a medicament for use in the treatment of GBM. U.S. Pat. No. 8,058,243 B2 discloses a method for treating a glioblastoma cancer involving neural precursor cells, early neural progenitor cells, neural stem cells (NSCs) or a combination thereof, the method comprising administering to a subject in need thereof a therapeutically effective amount of a composition comprising ifenprodil. Up to now, there is no single compound that can efficiently inhibit GBM tumor growth without other anti-tumor drugs.